Practice Essentials

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants which have largely fallen out of favor for the treatment of depression. However, their use is on the rise in the treatment of neurodegenerative diseases and they are still used in cases of refractory depression.

MAOI toxicity can occur in the following three ways:

Drug-food interactions - the so-called tyramine reaction

Overdose

Drug-drug interactions

All three mechanisms produce similar symptoms and signs, which stem from an excess of catecholaminergic neurotransmitters (see Pathophysiology). Clinical features include hypertension, tachycardia, tremors, seizures, and hyperthermia. (See Presentation.)

Because of the potential for severe toxicity and lack of effective antidotes, recognition of the disease, withdrawal of offending agents and aggressive decontamination is very important in patients with MAOI toxicity. Control of hyperthermia and fluid therapy are paramount. (See Treatment.)

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Background

Monoamine neurotransmitters (eg, epinephrine, norepinephrine, dopamine, serotonin) are stored in vesicles at the pre-synaptic nerve terminals and released through the plasma membrane into the synaptic cleft. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve and metabolized by intracellular monoamine oxidase (MAO) or destroyed by catechol-o-methyl transferase (COMT) in the synaptic cleft.

MAO has two isoforms: MAO-A and MAO-B. MAO-A is found primarily in the liver, gastrointestinal (GI) tract, and monoaminergic neurons. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are largely metabolized by MAO-A in the liver. Ingested monoamines, such as tyramine, are metabolized by MAO-A in the GI tract and liver.
[1] This shields the body from foods with high levels of tyramine, which have to potential to cause adrenergic hyperstimulation. This protective property of MAO-A is critical to the understanding of the most common cause of MAOI toxicity, drug-food interaction. The other isoform, MAO-B, is found primarily in the basal ganglia of the central nervous system and platelets.
[2]

One of the prevailing theories of depression is that its clinical features are related to decreased concentration of these neurotransmitters at the synapse.
[3] To address this, pharmaceuticals have been developed that either block the reuptake of neurotransmitters (eg, cyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs]) or interfere with the breakdown of the reabsorbed monoamines within the nerve terminal (monoamine oxidase inhibitors [MAOIs]).
[4]

First-generation MAOIs, such as phenelzine, isocarboxazid and tranylcypromine, are nonselective inhibitors. Second- and third-generation MAOIs tend to be specific inhibitors of either MAO-A or MAO-B. Specific MAO-A inhibitors are not commonly used, but have been studied in the treatment of depression. Specific MAO-B inhibitors have been studied in the treatment of both depression and neurodegenerative disorders. They are thought to have a better safety profile, as MAO-A activity in the gut is not inhibited. However, the selectivity of even the new MAOIs is dose related.
[1]

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Pathophysiology

Monoamine oxidase is responsible for the deactivation of monoamines such as epinephrine, norepinephrine, dopamine, serotonin and tyramine. When the inhibitory effects of MAOIs are amplified by overdose, drug-drug interactions, or drug-food interactions, the resulting increase of active monoamines are directly responsible for the manifestations of MAOI toxicity.

In a pure MAOI overdose, the ability of the neuron to degrade monoamines is severely diminished. As a result, the storage and release of monoamines is greatly increased. This effect can be potentiated or even enhanced by an additional property of MAOIs: even at therapeutic doses, MAOIs indirectly cause a release of norepinephrine into the synaptic space. Depending on the dose of the exposure, a hyperadrenergic crisis may ensue; 5 mg/kg of a non-selective MAOI can be life-threatening.
[1] This occurs uncommonly. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion but generally occur within 24 hours. These patients require prolonged close monitoring to prevent significant morbidity.

MAOI toxicity can be seen when an MAOI is combined with any drug that increases the synthesis, release, or effect of monoamines or decreases the metabolism or reuptake of monoamines. For a detailed list, see Causes.

The combination of an MAOI with a drug that increases serotonin levels can result in serotonin toxicity. This disease entity is similar to an adrenergic crisis from MAOI toxicity, but also features hyperreflexia and autonomic instability when severe. This constellation of symptoms is called serotonin syndrome.

Delayed presentations of MAOI toxicity are common, ranging from several hours to 24 hours for maximal toxicity, but symptoms can also be seen within minutes. Though MAOIs interact unfavorably with many medications, fatalities are rare with supportive care.
[1]

The most common MAOI toxicity results from interaction with tyramine-containing foods. When MAO found in the gut and liver (type A) is inhibited, ingested tyramine indirectly causes an amplification of adrenergic activity. It is usually rapid in onset, occurring within 15-90 minutes after ingestion. Most symptoms resolve in 6 hours. Fatalities are rare, but have been reported due to complications from hypertensive emergencies. See Causes for a detailed list of tyramine-containing foods.

Pharmacokinetics

MAOIs are absorbed well orally and peak plasma concentrations are reached within 2-3 hours. These drugs have a relatively large volume of distribution (1-5 L/kg) and are highly protein bound. They are metabolized by oxidation and acetylation in the liver and are excreted in the urine.

The two isoforms of MAO have different affinities for specific neurotransmitters. MAO-A is the primary metabolizer of norepinephrine. Dopamine and tyramine can be metabolized equally by MAO-A and MAO-B.
[2]

MAOIs bind irreversibly at their sites of action (moclobemide is an exception). By this binding, they are eliminated from circulation and, since they do not recirculate afterwards, their effects are not determined by their concentration in the blood. As it takes 2-3 weeks for enough new MAO to be synthesized, MAOIs have clinical effects for that amount of time after the last dose has been ingested. Third-generation MAOIs (not available in the United States) are reversible inhibitors and exist in a competitive equilibrium.
[5]

MAOIs absorbed through the gastrointestinal tract bind significantly to MAO in the gut mucosa and liver, producing a significant first pass effect. Thus, to produce their clinically desired effect in the central nervous system (CNS), MAOIs must be given in high enough doses to reach centrally-located MAO. A transdermal preparation of a selective MAO-B inhibitor, selegiline, appears to produce antidepressant effects with a significantly reduced risk for dietary-induced toxicity by bypassing the first pass effect of gut and hepatic MAOI effects.
[6, 7] At the lowest effective dosage of 6 mg/day, selegiline can be used without dietary modification.
[8]

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Epidemiology

United States

Reported exposures to MAOIs have decreased by more than 60% over the past 25 years. By year, the American Association of Poison Control Centers has reported the following number of cases involving MAOIs:

Depending on the year, 40%-50% of these cases were single exposures to MAOIs, with the remainder of the cases involving co-exposures. Death due to MAOI exposure is rare, with about one case reported per year over the past 10 years (including cases with both single and multiple exposures).

In 2015, there were 90 single exposures to MAOIs reported. Adults accounted for 71 cases, and 62 were known to be unintentional. Two cases (both involving tranylcypromine) had major outcomes. No deaths occurred due to single exposure to MAOIs in 2015. However, tranylcypromine was indicated as the primary cause of death in one case with multiple exposures.
[16]

The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAO has been found to play a central role in the pathogenesis of Alzheimer disease, and MAOIs are currently being studied as potential neuroprotective agents.
[17] If they prove effective for that purpose, their use—and episodes of toxicity—may well increase.

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Mortality/Morbidity

Severe toxicity is manifested by hyperthermia, seizures, respiratory depression, and CNS depression. Hypotension, cardiovascular collapse, and death may ensue but this is rare with supportive care. (See Epidemiology)

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Patient Education

All patients who are starting treatment with a monoamine oxidase inhibitor (MAOI) should receive extensive education regarding the potential for interactions with tyramine-containing foods and with other drugs. Patients should be encouraged to have all of their prescription and nonprescription drugs dispensed from one pharmacy so that an accurate medication profile can be maintained.

Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003 Feb. 64(2):208-14. [Medline].